The overall objective of this project is to test several hypotheses about the mechanism of opiate narcotic dependence formation. One hypothesis is that the central nervous system responds to overstimulation of opiate receptors by synthesizing or releasing an endogenous opioid antagonist substance which would account for abstinence symptoms opposite to the immediate effects of opiates. A second hypothesis is that this substance is the neuropeptide Cholecystokinin (CCK). The project will test the following experimental predictions which flow from one or both of these hypotheses. Cerebrospinal fluid from morphine abstinent rats will precipitate an immediate abstinence syndrome when injected into the ventricles of morphine dependent rats. This will be prevented by pretreatment with the CCK antagonist proglumide. Proglumide will partially alleviate opiate abstinence syndrome. Synthetic CCK will precipitate abstinence syndrome in dependent rats. Prolonger continuous infusion of CCK will cause a quasi-abstinence syndrome. Morphine dependent rats will have elevated cerebrospinal fluid levels of CCK. If an endogenous antagonist is ultimately confirmed and identified, it will become a major target in the treatment of opiate dependence.